Risk factors for cancer from the ambient environment are studied to identify specific chemicals and classes of contaminants, to investigate mechanisms of action, and to estimate the contribution of environmental factors to cancer in the general population. Exposures include drinking water contaminants, especially disinfection byproducts, nitrate, and arsenic; airborne radon in homes; residential levels and body burdens of chlorinated hydrocarbons; and emissions from industrial sources. Case-control studies in Iowa showed excess risks for rectal cancer in both sexes and bladder and brain cancers among men after long-term consumption of disinfection byproducts in drinking water. Analysis of these data with an improved and updated assessment of exposure to disinfection byproducts is ongoing. Bladder cancer in Spain was elevated after long-term exposure to disinfection byproducts, with enhanced risk among persons with genotypes GSTT1 (+) or GSTZ1 (with SNP rs1046428). It was also observed that risk of bladder cancer was associated with exposure to DBPs through routes other than ingestion (e.g., inhalation or dermal absorption). We are currently evaluating this hypothesis in a case-control study in New England. Nitrate levels in public water supplies in Iowa were not associated with risk of bladder and pancreas cancer. We observed increased risks of colon and kidney cancer among subgroups with increased nitrosation ability due to their higher intake of drinking water nitrate and lower and higher intakes of vitamin C and red meat, respectively. Ingestion of higher nitrate concentrations in public water supplies as well as higher dietary intake was associated with increased risk of thyroid cancer in the Iowa Womens Health study, a cohort study of older women in Iowa. Dietary nitrate intake was associated with hypothyroidism. Higher nitrate levels in private wells were associated with increased prevalence of subclinical hypothyroidism among women in a cohort study of Old Order Amish in Pennsylvania. Nested case-control studies are ongoing to evaluate polyhalogenated aromatic hydrocarbons in relation to risk of thyroid cancer. The major polybrominated diphenyl ether (PBDE) congeners were not associated with thyroid cancer risk in the PLCO cohort. Bladder cancer risk is increased after exposure to arsenic in drinking water supplies at levels several times the maximum contaminant limit. A case-control study in northern New England is evaluating bladder risk at lower levels that are more common in the United States. We have assigned a residential water supply arsenic concentration for 95% of participants residential person-years and 86% of occupational person-years. Carpet dust was used as an exposure indicator to examine the risk of childhood leukemia in relation to residential exposure to polychlorinated biphenyls (PCB) and organochlorine pesticides in a case control study in California. Significant positive trends in acute lymphocytic leukemia (ALL) risk were apparent with increasing concentrations of PCB congeners 118, 138, and 153. Summed levels of polybrominated diphenyls ethers (PBDEs) in carpet dust were not associated with ALL risk; however, risk was increased approximately 2-times for specific cctaBDE and decaBDEs including BDE-196, BDE-203, BDE-206 and BDE-207. We earlier found an association between PCBs in serum and household dust samples and risk of adult non-Hodgkin's lymphoma (NHL) in a multi-center study. We evaluated whether this relation is modified by immune gene variation for 3 exposures with elevated risk: PCB180 (plasma, dust measurements), the toxic equivalency quotient (TEQ) in plasma, and alpha-chlordane (dust measurements, self-reported termiticide use). Associations between all 3 exposures and NHL risk were limited to the same genotypes for IFNG (C-1615T) TT and IL4 (5'-UTR, Ex1-168CT) CC. Associations between PCB180 in plasma and dust and NHL risk were limited to the same genotypes for IL16(3'-UTR, Ex22+871AG) AA, IL8 (T-251A) TT, and IL10 (A-1082G) AG/GG. Many pesticides in current use around the home and in agriculture are not persistent in the body so biomarkers are not useful measures of long-term exposure. We compared concentrations of pesticides and other chemicals in dust samples collected by two methods, a specialized vacuum (the HVS3) and participant's own vacuum bag and found strong correlations for pesticides, PCBs, polycyclic aromatic hydrocarbons (PAH), and metals. Using a GIS in the case-control study of ALL, we refined metrics to evaluate agricultural pesticide use near residences, using information about the current and historical location of crops near homes. For specific agricultural pesticides use around homes in the prior two years showed the strongest relationship with concentrations in house dust compared with shorter time intervals. GIS-based pesticide metrics will be evaluated in relation to risk of ALL. Farm residence was associated with an increased risk of acute myeloid leukemia in the Iowa Womens Health Study cohort. Density of agricultural crops did not explain this association; however, row crop density within 750 m of homes was associated with elevated incidence of chronic lymphocytic leukemia/small lymphocytic lymphoma (RR increasing tertiles=1.4, 1.5 and 1.6) compared with women with no row crops. Residential proximity to specific industries reporting to the Environmental Protection Agency's Toxic Release Inventory was evaluated in the NHL case-control study. Increased risk was observed in relation to lumber/wood products especially for diffuse large B-cell lymphoma (lived within 2 miles: OR=1.7, 95% CI: 1.0-3.0). ORs were elevated for 10+ years living near chemical (OR=1.5, 95% CI: 1.1-2.0) and petroleum (OR=1.9, 95% CI: 1.0-3.6) industries. Proximity to emissions of dioxins/furans from cement kilns and hazardous waste incinerators was associated with higher concentrations in dust samples from homes. NHL risk was also increased with residential proximity to some dioxin/furan sources. Prior analyses showed increased risk of NHL with higher levels of PCBs in homes. Determinants of PCB levels in homes included population density, developed land near homes and the number of industrial facilities within 2 km, suggesting that outdoor sources of PCBs may be significant determinants of indoor concentrations. A case-control study of lung cancer and residential radon among Missouri women used a novel radon detector that integrated exposure over the past 30 years and observed significant excess lung cancer risk. A retrospective cohort study in Xuanwei, China demonstrated that annual tonnage and lifetime duration of smoky and smokeless coal use were positively associated with pneumonia mortality and that stove improvement was associated with a 50% reduction in pneumonia deaths and with decreased risk of lung cancer mortality in men (hazard ratio (HR)=0.62, 95% confidence interval (CI)=0.46-0.82) and women (HR=0.41, 95% CI=0.29-0.57). A case-control study in Xuanwei, China evaluated the risk of lung cancer by coal type and found a striking variation in risk of lung cancer from use of different types of coal in this region, with odds ratios varying from 1.1 up to 27.0. In a prospective cohort of urban women in Shanghai, poor kitchen ventilation was associated with a 49% increase in lung cancer risk (HR: 1.49; 95% CI: 1.15-1.95) compared to never having poor ventilation. Use of coal was not associated with risk; however, ever use of coal use with poor ventilation (HR: 1.69; 95% CI: 1.22-2.35) and 20 or more years of using coal with poor ventilation (HR: 2.03; 95% CI: 1.35-3.05) were also significantly associated with lung cancer risk highlighting an important public health issue in cities across China where people may have lived in homes with inadequate kitchen ventilation.